Esters of 3-(hydroxy or hydroxymethyl)-4-hydroxyphenyl aminomethyl ketones

ABSTRACT

Mono-, di- and tri-esters of 3-(hydroxy or hydroxymethyl)-4hydroxy-alpha-(aminomethyl)benzyl alcohols, obtained by methods involving reduction of the corresponding mono- and di-ester ketones, are useful for producing sympathomimetic effects, such as bronchodilation, of long duration with low cardiovascular stimulating effect, in warm-blooded mammals.

"United States Patent [191 Minatoya et al.

[451 Sept. 9, 1975 ESTERS OF 3-( HYDROXY OR HYDROXYMETHYL)-4-HYDROXYPHENYL AMINOMETHYL KETONES [75] Inventors: Hiroaki Minatoya, East Greenbush;

Benjamin F. Tullar, Chathan; Walter D. Conway, Amherst, all of [73] Assignee: Sterling Drug Inc., New York, NY.

[22] Filed: Mar. 12, 1971 [21] Appl. No.: 123,834

Related U.S. Application Data [63] Continuation-impart of Ser. No. 812,370, April 1,

1969, abandoned.

[30] Foreign Application Priority Data Mar. 16, 1970 Canada 077574 [52] U.S. Cl 260/473 R; 260/295 R; 260/410.5; 260/468 R; 260/468 G; 260/468 H; 260/469;

260/471 R; 260/473 G; 260/477; 260/479 R; 260/456 R; 260/488 CD; 424/308; 424/312 [51] Int. Cl. C07C 93/20; CO7C 69/76 [58] Field of Search 260/477, 473 R, 473 G, 260/469 Primary Examiner-Lorraine A. Weinberger Assistant Examiner-Paul J. Killos Attorney, Agent, or FirmB. Woodrow Wyatt; Paul E. Dupont [5 7] ABSTRACT 27 Claims, No Drawings ESTERS OF 3-HYDROXY(OR HYDROXYMETHYL)-4-HYDROXYPHENYL AMINOMETHYL KETONES This application is a continuation-in-part of our prior co-pending application Ser. No. 812,370, filed Apr. 1, 1969 and now abandoned.

This invention relates to compositions of matter classified in the art of chemistry as esters of 3-(hydroxy or hydroxymethyl)-4-hydroxy-alpha- (aminomethyl)benzyl alcohols, to a process and intermediates for the preparation of the same, and to a method for producing sympathomimetic effects, for instance, bronchodilation, of long duration in warmblooded animals by administering said esters.

The invention sought to be patented resides in one of its composition aspects in the chemical compounds designated as (A) esters of 3,4-dihydroxy-alpha- (aminoand N-substituted amino-methyl)benzyl alcohols which have in the free base form Formula 1 hereinbelow, and (B) esters of 3-hydroxymethyl-4-hydroxyalpha-( aminoand N-substituted amino-methyl)benzyl alcohols which have in the free base form Formula II hereinbelow:

wherein, in each of Formulas l and II:

R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;

R is hydrogen or alkyl having 1-3 carbon atoms;

Y is an acyl member which is alkanoyl having 1-22 carbon atoms, alkenoyl having one or two double bonds and having 4-22 carbon atoms, cycloalkyl- C,,H ,,CO- having a total of 4-10 carbon atoms of which 3-7 are ring carbon atoms in cycloalkyl and wherein n is zero, one or two, 1 -or 2- adamantanecarbonyl, phenoxyacetyl, naphthalenecarbonyl, pyridinecarbonyl, or Z-C,,H ,,-CO wherein n is zero, one or two and Z is phenyl or phenyl substituted by 1-3 members of the group consisting of alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2-8 carbon atoms, and alkanoylamino having 1-6 carbon atoms; and

Y and Y are the same or different and are hydrogen or one of the acyl members defined by Y, and v wherein in Formula I at least one of Y and Y' contains no less than four carbon atoms when R is tertbutyl or cycloalkyl and no less than seven carbon atoms when R is hydrogen or alkyl other than tert-butyl; and in Formula ll at least one of Y and Y contains no less than four carbon atoms.

These compounds are useful as long-acting sympathomimetic agents when administered orally, intratracheally, intraduodenally, or intravenously to warmblooded mammals.

The invention resides in another of its composition aspects in the chemical compounds designated as 3-(Y-O-)-4-(Y-O-)phenyl (R-NI-l-)(R)methyl ketones having in the free base phenol form the formula Formula II] and 3-(Y-O-CH )-4-(Y -O- )phenyl (R-NH-) (R' )methyl ketones having in the free base phenol form the formula Y--O--CH Formula [V wherein, in each of Formulas Ill and IV, R, R, Y, and Y have the same significance indicated hereinabove. These ester ketones'are useful as intermediates in the preparation of the alcohols of Formulas I and Il respectively hereinabove. I

The invention sought to be patented resides in one of its process aspects in the chemical process which comprises reducing an ester ketone having in the free base from Formula III or Formula 11V hereinabove to produce an ester alcohol having in free base form Formula I or Formula II respectively hereinabove wherein Y is hydrogen.

The invention sought to be patented resides in another of its process aspects in the chemical process which comprises monoor di-esterifying a 3,4- dihydroxyphenyl (R-NH-) (R')methyl ketone having in the free base form the formula Formula v or a 3-hydroxymethyl-4-hydroxyphenyl(R-Nl-l-) (R') methyl ketone having in'the free base phenol form the formula HO-CH Formula VI wherein in each of Formulas V and VI, R and R have the same significance indicated hereinabove, to produce an ester ketone having in the-free base form Formula III or Formula IV respectively hereinabove.

'The invention sought to be patented, in its method aspect, resides in the methodof producing sympathemimetic effects in a warm-blooded mammal' which comprises administering to said mammal an effective amount of a compound having in the free base form Formula I or Formula II hereinabove.

When R in the formulas herein is alkyl having 1-4 carbon atoms, there are included methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, tert-butyl and secbutyl.

When R in the formulas herein is cycloalkyl having 36 carbon atoms, there are included cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

When R in the formulas herein is alkyl having 1-3 carbon atoms, there are included methyl, ethyl, npropyl, and isopropyl. I

When Y, Y or Y in the formulas herein is alkanoy containing l-22 carbon atoms, there are included both unbranched and branched alkanoy], for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, 2-methylbutanoyl, pivalyl, 3-methylpentanoyl, 3,3-dimethylbutanoyl, 2,2-dimethylpentanoyl, docosanoyl, and 7,7-dimethyloctanoyl. The branched alkanoyl groups are preferred over the unbranched alkanoyl groups.

When Y, Y, or Y in the formulas herein is alkenoylhaving one or two double bonds and having 4-22 carbon atoms, there. are included, for example, crotonyl, 9-octadecenoyl, 2,5-hexadienoyl, 3,6-octadienoyl, 10, l 3-octadecadienoyl, and 5,13-docosadienoyl.

When Y, Y, or Y inthe formulas hereinis cycloalkyl-C,,I-I ,,CO-, there are included for example thecycloalkanecarbonyl and cycloalkanealkanoyl groups: cyclopropanecarbonyl, l-methylcyclopropanecarbonyl, cyclopropaneacetyl, alpha-methylcyclopropaneacety], l -methylcyclopropaneacetyl, Z-amylcyclopropaneacetyl, cyclopropanepropionyl, methylcyclopropanepropionyl,. 2-isobutylcyclopropanepropionyl, Z-hexylcyclopropanecarbonyl, cyclobutanepropionyl, 2-methylcyclobutanecarbonyl, l,- 3-dimethylcyclobutanecarbonyl, 3,3-dimethylcyclobutanecarbonyl, cyclobutaneacetyl, 2,2-dimethyl-3 ethylcyclobutaneacetyl, cyclobutanepropionyl, cyclopentanecarbonyl l-methyl-3-isopropylcyclopentanecarbonyl, cyclopentanepropionyl, cyclohexanecarbony], cyclohexaneacetyl, 4-methylcyclohexaneacetyl, cycloheptanecarbonyl, 4-methylcycloheptaneacetyl, and cycloheptanepropionyl.

When Y, Y, or Y in the formulas herein is (phenyl or substituted phenyl)-C,,H ,,CO, there are included for example ben zoyl, phenylacetyl, alphaalphaphenylpropionyl, beta-phenylpropionyl p-toluyl, m-

o-iodobenzoyl, m-bromobenzoyl, p-chlorobenzoyl, pfluorobenzoyl," 2-bromo-4-chlorobenzoyl, 2,4,6- trichlorobenzoyl, p-chlorop'henylacetyl, alpha-(mbromophenyl)propionyl, p-trifluoromethylbenzoyl, 2,- 4-di(trifluoromethyl)benzoyl,' m-trifluoromethylphenyl'acetyl beta-( p-trifluoromethylphenyl )propionyl, 2-methyl-4-methoxyben2oyl, 3-chloro- 4'ethoxybe'nzoyl, beta 3-methyl-4-chlorophenyl propionyl, p-dimethylaminobenzoyl, mdiethylaminobenzoyl p-dibutylaminobenzoyl, p-( N- methyl-N-ethylamino)benzoyl, m-propionamidobenzoyl, p-hexanoylaminobenzoyl, 3- chlo'ro 4 acetamidophenylacetyl, and p-acetamidophenylpropionyl'.

When Y, Y or Y in the formulas herein is naphthalenecarbonyl, there are included I naphthalenecarbonyl and 2-naphthalenecarbonyl.

When Y, Y, or Y in the formulas herein is pyridinecarbohyl, there are included picolinoyl (2- pyridinecarbonyl), nicotinoyl (3-pyridinecarbonyl), and isonicotinoyl (4-pyridinecarbonyl).

As provided above, in Formula I when R is tert-butyl or cycloalkyl, no more than one of Y and Y contains less than four carbon atoms; and when R is hydrogen or alkyl other than tert-butyl, no more than one of Y and Y contains less than seven carbon atoms. In Formula II at least one of Y and Y contains no less than four carbon atoms.

Due to the presence of the basic amino grouping, the free base forms of the final products represented by Formulas I and II and also of the intermediates represented by Formulas III and IV react with organic and inorganic acids to form acid-addition salts. The acidaddition salt forms are prepared from any organic or inorganic acid. They are obtained in conventional fashion, for instance either by direct mixing of the base with the acid, or, when this is not appropriate, by dissolving either or both of the base and the acid separately in water or an organic solvent and mixing the two solutions, or by dissolving both the base and the acid together in a solvent. The resulting acid-addition salt is isolated by filtration, if' it is insoluble in the reaction medium, or by evaporation of the reaction medium to leave the acid-addition salt as a residue. The acid moieties or anions in these salt forms'are in themselves neither novel not critical 'andtherefore can be any acid anion or acid-like substance capable of salt formation with the base.

"Representative acids for the formation of the acidaddition salts include formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tannic acid, glutamic acid, tartaric acid, oxalic acid, pyromucic acid, citric acid, lactic acid, glycolic acid, gluconic acid, saccharic acid, ascorbic acid, penicillin, benzoic acid, 'phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid, a'nthranilic acid, cholic acid, Z-pyridinecarboxylic acid, pamoic acid, 3-hydroxy-2- naphtholic acid, picric acid, quinic acid, tropic acid, 3-indoleacetic acid, barbituric acid, sulfamic acid, methanesulfonic acid, cthanesulfonic acid isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, butylarsonic acid, methanephosphonic acid, acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic o-acetamidobenzoyl,

5. acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, arsenic acid, and the like.

All of the acid-addition salts are useful as sources of the free base form, by reaction with an inorganic base. It will thus be appreciated that if one or more of the characteristics, such as solubility, molecular weight, physical appearance, toxicity, or the like of a given base or acid-addition salt thereof render that form unsuitable for the purpose at hand, it can be readily converted to another, more suitable form. For pharmaceutical purposes, acid-addition salts of the compounds of Formula I and Formula II with relatively non-toxic, pharmaceutically acceptable acid, for example hydrochloric acid, lactic acid, tartaric acid, and the like, are of course employed. r

The mono esters of. Formulas I and II wherein Y is hydrogen are of course amphoteric, having both free phenol and basic amino groups, and thus form salts with both acids and bases.

The manner and process of making and using the invention, and the best mode contemplated by the inventors of carrying out this invention, will now be described so as to enable any person skilled in the art to which it pertains to make and use the same.

The esters of Formula I hereinabove wherein Y is hydrogen are obtained in accordance with the invention by reducing an ester ketone of Formula III. Similarly, the esters of Formula II hereinabove wherein Y is hydrogen are obtained by reducing an ester-ketone of Formula IV. As will of course be appreciated, in effecting reduction of these ester-ketones of Formulas III and IV to the corresponding ester-alcohols, the useof reducing means resulting in reduction of carboxylic ester groupings must be avoided. Ordinarily, it is preferred to effect the desired reduction either by catalytic hydrogenation in the presence of a noble metal catalyst such as platinum or palladium, or by employing an alkali metal borohydride and a lower alkanol. In those instances where one or both of Y and Y in the esterketones of Formulas III and IV contain an olefinic double bond, and it is desired to retain this unsaturation in the reduction product'(Formula I or II wherein Y is hydrogen), the borohydride method is used since, as is well known, catalytic hydrogenation effects reduction of such double bonds.

The catalytic hydrogenation process is conveniently carried out in a suitable solvent, for example ethyl alcohol, at -60C. under pressure, for instance on the order of 205O pounds of hydrogen pressure per square inch, in the presence of palladium or platinum hydrogenation catalyst. The hydrogenation iscontinued until the theoretical amount of hydrogen is absorbed as calculated in conventional fashion from drop in hydrogen pressure. A hydrogenation time of 4 hours or less is generally satisfactory. After removal of the catalyst, the isolation of the ester-alcohol product is effected in conventional manner, as by evaporation of some or all of the solvent from the reaction mixture, collecting the precipitated crude ester-alcohol, and purifying it by recrystallization from a suitable solvent.

In some instances, when applied to the ester ketones The ester-ketones of Formulas III and IV used as starting materials in the reduction process described hereinabove are obtained by monoor di-esterifying the corresponding known and readily available 3,4- dihydroxyphenyl (R-NH-)(R")-methyl ketones of Formula V and 3-hydroxymethyl-4-hydroxyphenyl (R-NI-I- )(R')methyl ketones of Formula VI, respectively. When R is hydrogen, methyl, or ethyl, to prevent undesired N-acylation it is advantageous to N-benzylate (N,N-dibenzylate when R is hydrogen) the ketone of Formula V before the esterification is carried out. These protective N-benzyl groups can of course be readily removed by catalytic: hydrogenation either at the ester ketone stage or at the ester alcohol stage (final product), as desired.

For the production of the mono-ester ketones of Formula III wherein Y is hydrogen, the starting 3,4- dihydroxyphenyl (R-NH-)(Rl'-)methyl ketone (Formula V) is treated with one molecular equivalent of an acid anhydride or an acid halide of the appropriate carboxylic acid (Y-OH wherein Y has the significance indicated hereinabove), optionally but preferably in the presence ofan acid-absorbing medium, in any suitable manner for the acylation of phenolic hydroxyl. In one preferred procedure, the 3,4-dihydroxyphenyl (R-NH- )(R)methyl ketone (Formula V) is treated with two molecular equivalents of an alkali metal lower alkoxide, for instance sodium methoxide, and the resulting alkali metal phenolate is treated with one molecular equivalent of the appropriate acid halide, Y-halogen wherein Y has the same significance indicated hereinabove, for instance the acid chloride, Y-Cl. The 4- hydroxy group'in the starting 3,4-dihydroxyphenyl (R- NH-)(R)methyl ketone (Formula V) is more readily acylated than the 3-hydroxyl group, and thus the monoacylation produces the desired 3-hydroxyphenyl-4- acyloxyphenyl (R-NI-I-)(R)methyl ketone (Formula III wherein Y is hydrogen).

The mono-ester ketones of Formula IV wherein Y is hydrogen are readily obtained! either by selectively esterifying the alcoholic hydroxyl without esterifying the phenolic hydroxyl or by selectively mono-deacylating the diester (obtained as indicated hereinbelow) to convert the 4-acyloxy group to 4-hydroxyl while leaving the 3-acyloxymethyl group intact. The selective esterification is conveniently effected by reacting the ketone of Formula VI with one mole equivalent of a mixed anhydride of the formula YCOO-COCF wherein Y has the same significance indicated hereinabove, in trifluoroacetic acid. If desired, it is satisfactory and ordinarily more convenient to form the mixed anhydride in situ by mixing the appropriate acid chloride, YCl, with trifluoroacetic acid. In the selective mono-deacylation method, a diester of Formula IV wherein Y is an acyl group is treated at room temperature with a relatively weak organic base such as benzylamine or 2-phenylcyclopropylamine in N,N-dimethylformamide, dimethylsulfoxide, or similar solvent,

whereby there is obtained the desired mono-ester of Formula IV where Y is hydrogen.

The di-ester ketones of Formula III and IV wherein both of Y and Y are acyl groups are obtained by acyl ating the 3-hydroxy-4-acyloxyphenyl(R-NI-I- )(R")methyl ketones (Formula III wherein Y is hydrogen) and the 3-(acyloxymethyl)-4-hydroxyphenyl (R- NH-)(R)methyl ketones (Formula IV wherein Y is hydrogen, obtained as above-described, with one molecular equivalent of an acid anhydride or an acid halide of the appropriate carboxylic acid (YOH) which is either different from or the same as the acylating agent used in the first acylation step. As will be appreciated, when it is desired that Y and Y in the di-ester ketone (Formula III and Formula IV) be identical, it is generally more convenient to prepare these products by introducing both acyl groups in a single procedure by employing two molecular equivalents of the acylating agent, and thereby proceed directly to the desired diester ketone without isolation of the intermediatelyformed mono-ester ketone. When the alkali metal phenolate method is employed, the starting 3,4- dihydroxyphenyl (R-NH-)(R)-methyl ketones of Formula V are of course reacted with two molecular equivalents of alkali metal lower alkoxide so as to replace both of the phenolic hydrogens with the alkali metal, whereas the 3-hydroxymethyl-4-hydroxyphenyl (R- NH-)(R')methyl ketones of Formula VI require use of only one molecular equivalent of alkali metal alkoxide.

In the preparation of the di-ester ketones of Formula IV, a procedure alternative to the one above-described comprises forming a 3(acyloxymethyl)-4-acyloxyalpha-(R)-acetophenone, brominating to produce a 3-( acyloxymethyl )-4-acyloxy-alpha-( R )-alphabromoacetophenone, and aminating this product at very low temperature, preferably in the range C. to 60C. with the appropriate aminating agent having the formula R-NI-I wherein R has the same significance indicated hereinabove. For the preparation of monoesters of Formula IV wherein Y is hydrogen, this method is readily modified by selective removal of the 4-acyloxy group by treating the 3-(acyloxymethyl)-4- acyloxy-alpha-(R')-acetophenone with benzylamine, or the like weak organic base, in N,N-dimethylformamide, dimethyl sulfoxide, or similar solvent, and subjecting the resulting 3-acyloxymethyl-4-hydroxy-alpha- (R)-acetophenone to the bromination and amination steps as indicated. Alternatively, if it is desired to obtain a mixed di-ester of Formula IV wherein Y and Y are different acyl groups, the 3-acyloxymethyl-4- hydroxy-alpha-(R)-acetophenone is appropriately acylated to yield a 3-acyloxymethyl-4-acyloxy-alpha- (R)-acetophenone wherein the acyl groups are different and thereafter subjecting this product to the indicated bromination and amination procedures.

The preparation of the esters of Formula I and Formula II wherein Y is acyl are obtained generally by esterification of the corresponding ester-alcohols of Formula I and Formula II wherein Y is hydrogen. This esterification is conveniently effected by treatment of an acid(strong)-addition salt of the ester-alcohol, for instance a hydrohalide or methanesulfonate salt, with the appropriate acid halide of formula Y-halogen, preferably the acid halide, Y-Cl, wherein Y has the same significance indicated hereinabove.

The esters of Formula II wherein Y is hydrogen and Y is acyl are alternatively obtained by preferential hydrolysis of the triesters of Formula II wherein Y Y, and Y are each acyl to convert the 4-acyloxy group to 4- hydroxy while leaving the other two ester groups intact.

The esters of this invention, having as aboveindicated in free base form the Formulas I and II, when administered orally, intratracheally, intraduodenally, or intravenously to warm-blooded mammals are useful for producing sympathomimetic effects of substantially longer duration than the corresponding unesterified sympathomimetic agents.

Generally speaking, the di-esters of Formula I and Formula II (wherein Y is acyl) have longer duration of sympathomimetic action than the corresponding mono-esters of Formula I and Formula II (wherein Y is hydrogen). Particularly preferred embodiments of this invention are the esters of the sympathomimetic agents, for instance 3,4-dihydroxy-alpha-(isopropylaminomethyl)benzyl alcohol and especially 3,4- dihydroxy-alpha-(tert-butylaminomethyl)benzyl alcohol, which have useful bronchodilator action. These particularly preferred esters, which are those having Formula I wherein R is hydrogen and R is isopropyl or tert-butyl, not only have longer duration of bronchodilator action than the corresponding unesterified bronchodilator agents, when administered orally, intratracheally, intraduodenally, or intravenously to warmblooded mammals but also advantageously produce lower cardiovascular effects than the corresponding unesterified compounds. In this group of preferred esters the diesters especially those wherein one of Y and Y is benzoyl or substituted benzoyl and the other is benzoyl, substituted benzoyl, or alkanoyl, afford special advantages.

In carrying out the method aspect of this invention, i.e. the method of producing sympathomimetic effects of long duration in warm-blooded mammals which comprises administering to said mammal an effective amount of an ester having in the free base form Formula I or Formula II hereinabove, the said esters are orally administered in the same manner as the known corresponding unesterified sympathomimetic. Thus, they can be used with any of the pharmaceutically acceptable carriers conventionally employed for oral or parenteral administration of such agents. Ordinarily, they are combined with conventional pharmaceutical solid or liquid diluents and carriers in tablets, capsules, syrups, emulsions, solutions, suspensions or the like. The formulations may contain any of the usual excipients as water, lactose, starch, magnesium stearate, talc, gelatin, calcium carbonate, gums, and the like. An especially preferred method for administering these esters (Formula I and Formula II) is in the form of an aerosol inhalent preparation, for example of the general type conventionally used in aerosol therapy, as in the treatment of bronchospasms, wherein a sympathomimetic agent with effective bronchodilator activity is incorporated with suitable carriers and an inert propellent in a nebulizing unit. A typical formulation of the aerosol type contains, by weight: 0.25 per cent of the ester (Formula I or Formula II) or a suitable pharmaceutical]y-acceptable salt thereof, 39.75 per cent of U.S.P. ethanol, 48 per cent of dichlorotetrafluoroethane, and 12.00 per cent of dichlorodifluoromethane.

The individual unit dosage can be varied as desired. For general use it is preferred to incorporate, in a solid vehicle, tablet or capsule, about 0.1 to mg. of the ester (Formula I or Formula II); or in a liquid vehicle, about 0.1 to 100 mg. of the ester (Formula I or Formula II) per teaspoonful or, in an aerosol, 0.02 to 2 mg. per actuation. The effective oral dose for producing bronchodilation is in the approximate range 0.0022.0 mg./kg.

This invention is illustrated by the following examples without, however, being limited thereto.

EXAMPLE 1 A. A mixture of 25 g. of 3,4-dihydroxyphenyl N-tertbutylaminomethyl ketone hydrochloride, 150 ml. of butyric acid saturated with hydrogen chloride, and 150 ml. of butyryl chloride was stirred on a steam bath until a clear solution was obtained (in about 6 hours) and the solution was heated on the steam bath for one hour. Approximately 50 ml. of solvent was distilled under reduced pressure from the reaction mixture which was then cooled. The mixture was filtered to collect a crystalline solid product which was washed well with diethyl ether and sucked dry under a rubber dam overnight. There was thus obtained 31 g. of 3,4-bis(- butyryloxy)phenyl N-tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 2l2215C. (dec.)(uncorr.).

B. A mixture of 30 g. of 3 ,4-bis(butyrylxy)phenyl N- tert-butylaminomethyl ketone hydrochloride, 200 ml. of 90 per cent ethyl alcohol, and 2 g. of 10 per cent palladium-on-charcoal hydrogenation catalyst was hydrogenated for 2 hours at 50C. under an initial hydrogen pressure of 50 pounds per square inch. The hydrogenation mixture was filtered to remove the catalyst. The solvent was evaporated from the filtrate under reduced pressure and the resulting residue was taken up in 50 ml. of isopropyl alcohol, allowed to stand overnight at C., and filtered to remove 3 g. of solid. The filtrate was evaporated under reduced pressure, the residue thus obtained was dissolved in 50 ml. of isopropyl acetate, and this solution was filtered to remove a small amount of insoluble solid. When the filtrate was diluted with anhydrous diethyl ether, a solid separated from solution. This solid was collected on a filter. There was thus obtained 20 g. of crude 3,4- bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride. This salt was dissolved in water and then ammonium hydroxide was added, resulting in precipitation of the free base, 3,4-bis(butyryloxy)- alpha-(tert-butylaminomethyl)benzyl alcohol. This precipitate was collected on a filter and washed well first with water and then with n-hexane. This base, which melted at 9799C. (uncorr.), was dissolved in isopropyl alcohol and this solution was concentrated under reduced pressure. The resulting residue was dissolved in 30 ml. of isopropyl acetate and there was added ethereal hydrogen chloride solution in an amount affording a slight excess of the required amount of hydrogen chloride for conversion of the base to the hydrochloride. The mixture was cooled and the inside of the container was scratched to induce crystallization. The mixture was diluted with 100 ml. of diethyl ether and the solid precipitate was collected on a filter and washed with anhydrous diethyl ether and dried at 70 C. There was thus obtained 11 g. of 3,4- b .is( butyryloxy )-alpha-( text-butylaminomethyl )benzyl alcohol hydrochloride as a white crystalline solid which melted at 136138C. (uncorr.). This salt was soluble in water to the extent of at least 20 per cent. The pH of a 1 per cent aqueous solution of this salt was 6.0; and a precipitate formed when the pH of this solution was raised to 7.0 by addition of N/ sodium hydroxide solution.

EXAMPLE 2 A. To a mixture of 26 g. of 3,4-dihydroxyphenyl tertbutylaminomethyl ketone hydrochloride in 200 ml. of

N,N-dimethylformamide under an atmosphere of nitrogen there was added 17 g. of sodium methoxide. By distillation under reduced pressure, 50 ml. of liquid was removed and the mixture was then cooled and under an atmosphere of nitrogen 25 g. of isobutyryl chloride was added rapidly at 525C. The reaction mixture was stirred at 25C. for 1 hour and then was warmed to C. and the solvent was removed by distillation. The resulting residue was slurried in 400 ml. of diethyl ether, and the slurry was filtered to remove about 10 g. of insoluble solid. The ethereal layer in the filtrate was separated, washed with dilute aqueous sodium hydroxide solution and then with water. There was thus obtained an ether solution of 3,4-bis(isobutyryloxy)phe nyl tert-butylaminomethyl ketone. To this solution there was added a solution obtained by adding 4 ml. of hydrochloric acid to 25 ml. of water, and the resulting mixture was shaken. The crystalline solid which formed was collected on a filter and dried at 70C. There was thus obtained 8.5 g. of 3,4-bis(isobutyryloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline powder which melted at 221223C. (dec.- )(uncorr.).

B. By catalytic hydrogenation of 8.5 g. of 3,4-bis- (isobutyryloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of per cent ethyl alcohol in the presence of 2 g. of 10 per cent palladium-oncharcoal catalyst there was obtained 5.0 g. of 3,4- bis(isobutyryloxy)-alpha-(tertbutylaminomethy])benzyl alcohol hydrochloride as a white crystalline powder which melted at 190C. (uncorr.).

EXAMPLE 3 A. A mixture of 25 g. of 3,4-dihydroxyphenyl tertbutylaminomethyl ketone hydrochloride, g. of isovaleryl chloride, and 100 g. of isovaleric acid was stirred on a steam bath for 72 hours. The reaction mixture was allowed to stand overnight at room temperature (approximately 25C.) and then was heated and filtered while hot to remove 18 g. of solid. The filtrate was evaporated to dryness under reduced pressure and the resulting residue was crystallized from isopropyl acetate containing a small amount of acetic acid. There was thus obtained 1 1.2 g. of 3,4-bis(isovaleryloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white cyrstalline solid which melted at 220-222C. (uncorr.). After recrystallization of a sample of this compound from isopropyl alcohol the melting point was 224225C.

B. By catalytic hydrogenation of 11.2 g. of 3,4-bis- (isovaleryloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 250 ml. of 95 per cent ethyl alcohol in the presence of 2 g. of 10 per cent palladium-oncharcoal catalyst there was obtained 3.6 g. of 3,4- bis( isovaleryloxy )-alpha-( tert-butylaminomethyl benzyl alcohol hydrochloride as a white crystalline powder which melted at 173C. (uncorr.). This salt was soluble in water at 25C. to the extent of at least 20 per cent. The pH of a 1 per cent aqueous solution was 5.4; and when the pH of this solution was adjusted to 7.0 by addition of N/ 10 sodium hydroxide solution, a precipitate fonned.

EXAMPLE 4 A. A mixture of 26 g. of 3,4-dihydroxyphenyl tertbutylaminomethyl ketone hydrochloride, 50 g. of 2- methylbutanoyl chloride, 100 g. of Z-methylbutanoic acid, and 0.5 g. of aluminum chloride was heated with vigorous stirring at 120C. for 1 hour. Then, since evolution of hydrogen chloride from the reaction mixture had slowed considerably, the mixture was heated at 145C. for 2 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was slurried in 300 ml. of boiling acetone, and the slurry was filtered. The solid thus collected, which was 3,4-bis( 2-methylbutanoyloxy)-phenyl I tertbutylaminomethyl ketone hydrochloride, weighed 30 g. and melted at 21 822lC. (uncorr.).

B. By catalytic hydrogenation of 29.5 g. of 3,4-bis( 2- methylbutanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of 95 per cent ethyl alcohol in the presence of 2 g. of 10 per cent palladium-oncharcoal catalyst there was obtained 26 g. of 3,4-bis(2- methylbutanoyloxy )-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride as a white crystalline powder which melted at 163l65C. (uncorr.). The solubility of this salt in water at C. was at least 5 per cent.

EXAMPLE 5 A. Proceeding in a manner similar to that described in part A of Example 2 above, 17 g. of sodium methoxide was interacted with 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloridein 200 ml. of N,N-dimethylformamide and the resulting sodium phenolate salt was interacted with 24 g. of pivalyl chloride (alternatively designated as trimethylacetyl chloride or 2,2-dimethylpropanoyl chloride). From this ac ylation reaction there was obtained 3,4-bis(pivalyloxy)phenyl tert-butylaminomethyl ketone which was treated with hydrochloric acid to yield 11.5 g. of.

3 ,4-bis( pivalyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which EXAMPLE 6 A. Proceeding in a manner similar to that described in Example lA above, 10.4 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride, 24 ml. of 3-methylpentanoyl chloride, and ml. of 3- methylpentanoic acid were interacted to yield 4.5 g. of 3 ,4-bis( 3-methylpentanoyloxy )phenyl tertbutylaminomethyl ketone hydrochloride as a white crystalline solid which melted at l39140C. (uncorr.).

B. By catalytic hydrogenation of 4.5 g. of 3,4-bis(3- methylpentanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 100 ml. of anhydrous ethyl alcohol in the presence of 0.5 g. of 10 per cent palladiumon-charcoal catalyst there was obtained 2.7 g. of 3,4- bis( 3-methylpentanoyloxy)-alpha-( tertbutylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at l39-l40C. (uncorr. This salt was soluble in water at 25C. to the extent of at least 5 per cent.

EXAMPLE 7 alcohol in the presence of 2 g.'of 10 per cent palladiumon-charcoal catalyst there was obtained 6.0 g. of 3,4- bis( 3 ,3-dimethylbutanoyloxy )-alpha-( tertbutylaminomethyl)benzyl alcohol hydrochloride as a white crystalline powder which melted at 226C. (uncorr. This salt was soluble in water at 25C. to the extent of at least l per cent.

EXAMPLE 8 A. Proceeding in a manner similar to that described in' Example 2A above, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was interacted with 18 g. of sodium methoxide, and the resulting sodium phenolate salt was interacted with 30 ml. of 2,2-dimethylpentanoyl chloride to yield 17 g. of 3,4- bis( 2 ,Z-dimethylpentanoyloxy )phenyl tertbutylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 183185C. (uncorr.). I

B. By catalytic hydrogenation of 15 g. of 3,4-bis(2,2- dimethylpentanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of per cent ethyl alcohol in the presence of 2 g. of 10 per cent palladiumon-charcoal catalyst there was obtained 3,4-bis(2,2- dimethylpentanoyloxy )-alpha-( tertbutylaminomethyl)benzyl alcohol hydrochloride which by treatment with an excess of 10 per cent ammonium hydroxide was converted to the freebase (l l g.). This base was converted to its methanesulfonic acid salt (10g.), a white crystalline powder which melted at l07lO9C. (uncorr.) The methanesulfonate was soluble in water at 25C. to the extent of at least 5 per cent.

EXAMPLE 9 Following the procedure described above in Example 2A but using decanoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis( decanoyloxy )-phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt as a white crystalline solid which decomposed slowly above 235C. (uncorr.). When this hydrochloride was catalytically hydrogenated, using the procedure described above in Example 28, there was obtained 3,4-bis(decanoyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride which was converted to the corresponding free base, a crystalline whilte solid, mp. 73-74C. (uncorr.), and this base was converted to the methanesulfonate salt, a crystalline white solid, mp 4548C. (uncorr.).

EXAMPLE 10 Following the procedure described above in Example 2A but using tetradecanoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(tetradecanoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained 3 ,4-bis( tetradecanoyloxy -alpha-( tert butylaminomethyl)benzyl alcohol methanesulfonate.

EXAMPLE 1 1 Following the procedure described above in Example 2A but using octadecanoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(octadecanoylox y)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt as a white crystalline solid, m.p. l80l85C. (uncorr.). When 14 g. of this hydrochloride was catalytically hydrogenated, using the procedure described above in Example 23, there was obtained 3,4-bis(octadecanoyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride as a white solid which melted at 7578C. (uncorr.). This hydrochloride was converted to the base by treatment with ammonium hydroxide, and the base was extracted with diethyl ether. The ethereal solution thus obtained was dried over anhydrous calcium sulfate and then treated with 1.5 g. of methanesulfonic acid to yield 6.3 g. of 3,4-bis-(octadecanoyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at l05-108C (uncorr.).

EXAMPLE 12 Following the procedure described above in Example 2A but using docosanoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(docosanoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using the procedure described above in Example 28, there is obtained 3,4- bis(docosanoyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol methanesulfonate.

EXAMPLE 13 A. A mixture of 5.2 g. of 3,4-dihydroxy tertbutylaminomethyl ketone hydrochloride, ml. of l-methylcyclopropanecarbonyl chloride, and ml. of l-methylcyclopropanecarboxylic acid was stirred at 120C. under slight pressure. After evolution of hydrogen chloride had slowed considerably, the temperature of the reaction mixture was raised to 140C. for minutes. Approximately 10 ml. of solvent was distilled from the mixture and the residue, which contained a crystalline solid, was mixed with anhydrous diethyl ether and filtered. The solid thus collected, which weighed 7.5 g., was slurried in a waterdiethyl ether mix ture and the slurry was made basic by addition of ammonium hydroxide. The ether layer was separated, washed with dilute sodium hydroxide solution and then with water, and was shaken with a solution prepared by diluting 3 ml. of concentrated hydrochloric acid to 30 ml. with water. The solid which precipitated was collected on a filter, washed with diethyl ether, and dried at C. to yield 6.5 g. of 3,4-bis-( lmethylcyclopropanecarbonyloxy)phenyl tertbutylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 253255C. (dec.- )(uncorr.).

B. By catalytic hydrogenation of 6.1 g. of 3,4-bis( lmethylcyclopropanecarbonyloxy)phenyl tertbutylaminomethyl ketone hydrochloride in 200 ml. of per cent ethyl alcohol in the presence of 2 g. of 10 per cent palladium-on-charcoal catalyst there was obtained 2.6 g. of 3.4-bis( lmethylcyclopropanecarbonyloxy)-alpha-(tertbutylaminomthyDbenzyl alcohol hydrochloride as a white crystalline powder which melted at 2l0212C. (uncorr.).

EXAMPLE 14 When cyclopropanecarbonyl chloride and cyclopropanecarboxylic acid are substituted for the l-methylcyclopropanecarbonyl chloride and lmethylcyclopropanecarboxylic acid, respectively, in the procedure described in Example 13A above, the acylation product obtained is 3,4-bis(cyclopropanecarbonyloxy)phenyl tert-butylaminomethyl ketone hydrochloride; and when this product is catalytically hydrogenated using the procedure described in Example 13B above, there is obtained 3,4- bis(cyclopropanecarbonyloxy)alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 1 5 layer was separated, washed successively with water,

dilute aqueous sodium hydroxide solution, and water, and dried over anhydrous calcium sulfate. Ethereal hy* drogen chloride solution was added to the dry ether solution and the solid which precipitated was collected on a filter. The product thus collected was recrystallized from 200 ml. of isopropyl alcohol to yield 1 l g. of 3,4- bis(cyclohexanecarbonyloxy)phenyl tertbutylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 204-2l0C. (dec.) (uncorr.).

B. By catalytic hydrogenation of 10.6 g. of 3,4-bis- (cyclohexanecarbonyloxy )phenyl tertbutylaminomethyl ketone hydrochloride in ml. of anhydrous ethyl alcohol in the presence of 1.0 g. of 10 per cent palladium-on-charcoal catalyst there was obtained 8.2 g. of 3,4-bis(cyclohexanecarbonyloxy)- alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at 2l2-2 l3C. (uncorr.). The solubility of this salt in each of water and polyethylenegllycol at 25C. was less than 0.1 per cent. When a l per cent solution of this salt in dimethyl sulfoxide was diluted with three volumes of water, no precipitate formed.

EXAMPLE 16 When cyclobutanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis-(cyclobutanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above there is obtained 3,4- bis( cyclobutanecarbonyloxy )-alpha-( tertbutylaminomethyl )-benzyl alcohol.

EXAMPLE 1 7 When cyclopentanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(cyclopentanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 158 above, there is obtained 3,4- bis(cyclopentanecarbonyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol.

EXAMPLE 18 When cycloheptanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(cycloheptanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15 B above, there is obtained 3,4- bis(cycloheptanecarbonyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol.

EXAMPLE 19 When 2-hexylcyclopropanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis( 2- hexylcyclopropanecarbonyloxy)phenyl tertbutylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4- bis(2-hexylcyclopropanecarbonyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol.

EXAMPLE 20 EXAMPLE 21 When 1,3-dimethylcyclobutanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is dimethylbutanecarbonyloxy)phenyl tert butylaminomethyl ketone; and when this product is 3,4-bis( 1,3-

catalytically hydrogenated using the procedure described in Example 153 above, there is obtained 3,4- bis( l,3-dimethylcyclobutanecarbonyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol.

EXAMPLE 22 When 2-amylcyclopropaneacetyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis( 2-amylcylopropaneacetoxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 158 above, there is obtained 3 ,4-bis( 2-amylcyclopropaneacetoxy )-alpha- (tert-butylaminomethyl)benzyl alcohol.

EXAMPLE 23 When 2,2-dimethyl-3-ethylcyclobutaneacetyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(2,2-dimethyl- 3-ethylcyclobutaneacetoxy )phenyl tertbutylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 158 above, there is obtained 3,4- bis( 2,2-dimethyl-3-ethylcyclobutaneacetoxy )-alpha- (text-butylaminomethyl)benzyl alcohol.

EXAMPLE 24 Following the procedure described above in Example 15A but using cyclohexaneacetyl chloride instead of cyclohexanecarbonyl chloride the acylation product obtained is 3,4-bis(cyclohexaneacetoxy)phenyl tertbutylaminomethyl ketone; and when this product is catalytically hydrogenated, using the procedure described above in Example 158, there is obtained 3,4- bis(cyclohexaneacetoxy)-alpha-(tertbutylaminomethyl )benzyl alcohol.

EXAMPLE 25 When 4-methylcycloheptaneacetyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(4-methylcycloheptaneacetoxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(4- methylcycloheptaneacetoxy)-alpha-(tertbutylaminomethyl)benzyl alcohol.

EXAMPLE 26 When 2-isobutylcyclopropanepropionyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A, above, the acylation product obtained is 3 ,4-bis( 2- isobutylcyclopropanepropionyloxy )phenyl tertbutylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 158 above, there is obtained 3,4- bis( 2-isobutylcylopropanepropionyloxy )-alpha-( tertbutylaminomethyl )benzyl alcohol.

EXAMPLE 27 Following the procedure described above in Example 15A but using cycloheptanepropionyl chloride instead of cyclohexanecarbonyl chloride the acylation product obtained is 3,4-bis(cycloheptanepropionyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated, using the procedure described above in Example B, there is obtained 3,4- bis( cycloheptanepropionyloxy )-a1pha-( tertbutylaminomethyl)benzyl alcohol.

EXAMPLE 28 Following the procedure described above in Example 15A but using alpha-methylcyclopropaneacetyl chloride instead of cyclohexanecarbonyl chloride the acylation product obtained is 3,4-bis(alpha-methylcyclopropaneacetoxy)pheny1 tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated, using the procedure described above in Example 15B, there is obtained 3 ,4-bis( alphamethylcyclopropaneacetoxy)-alpha-(tertbuty1aminomethy1)benzyl alcohol.

EXAMPLE 29 A. To 26 g. of 3,4-dihydroxyphenyl tertbutylaminomethyl ketone hydrochloride in 200 ml. of dioxane there was added rapidly g. of potassium hydroxide in 50 ml. of methanol. One-half of the solvent was distilled from the resulting mixture under reduced pressure and then 29 g. of benzoyl chloride was dripped in at 510C. during a period of '30 minutes. The reaction mixture was stirred for another half-hour at 10C., after which the solvent was distilled off under reduced pressure. The residue thus obtained was slurried with a mixture of 100 ml. and 400 m1. of diethyl ether, and the slurry was filtered to remove 12 g. of insoluble solid. The ether layer in the filtrate was separated, washed with water, dilute aqueous sodium hydroxide solution, and water, and then was shaken with a solution of 7 ml. of concentrated hydrochloric acid in 50 ml. of water. The mixture was cooled in ice and the pre cipitate which formed was collected on a filter and washed with a few ml. of water and then with diethyl ether, and dried at 70C. There was thus obtained 1 1.0 g. of 3,4-bis(benzoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 215218C. (dec.) (uncorr.).

B. By catalytic hydrogenation of 1 1 g. of 3,4-bis(benzoyloxy)pheny1 tert-butylaminomethyl ketone hydrochloride in 200 ml. of anhydrous ethyl alcohol in the presence of 1.0 g. of 10 per cent palladium-oncharcoal catalyst there was obtained 6.0 g. of 3,4- bis( benzoyloxy )-a1pha-( tert-butylaminomethyl )benzyl alcohol hydrochloride which crystallized from a diethyl etheracetic acid-isopropyl acetate mixture as a white solid which melted at 214216C. (uncorr.). The solubility of this salt in each of dimethylsulfoxide and glycerol formal at C. was 1 per cent or more; and when a l per cent solution of this salt in each of these so]- vents was diluted with three volumes of water, no precipitate formed in either instance.

EXAMPLE A. Under an atmosphere of nitrogen, 26 g. of 3,4- dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was mixed with 17 g. of sodium methoxide in 200 m1. of N,N-dimethylformamide and 50 ml. of solvent was distilled off below 40C. under reduced pressure. Then 31 g. of p-toluyl chloride was dripped in at -10C. The solvent was distilled from the reaction mixture under reduced pressure, the resulting residue was slurried in a mixture of water and diethyl ether, and the slurry was filtered to remove 9.5 g. of insoluble solid. The ether layer in the filtrate, which contained 3,4-bis(p-toluyloxy)phenyl tert-butylaminomethyl ketone, was separated, washed with water and dilute sodium hydroxide, and then was shaken with a solution obtained by diluting 4 ml. of concentrated hydrochloric acid with water to a volume of 30 ml. After the mixture had stood for 1 hour at room temperature, the precipitate which had formed was collected on a filter, washed with diethyl ether, and recrystallized from isopropyl alcohol. There was thus obtained 14.0 g. of 3,4-bis(ptoluy1oxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 221224C. (uncorr.). The solubility of this salt in. water at 25C. was less than 0.1 per cent.

B. By catalytic hydrogenation of 13.5 g. of 3,4-bis(pto1uyloxy)pheny1 tert-butylaminomethyl ketone hydrochloride in 220 ml. of anhydrous ethyl alcohol at room temperature in the presence of 2.0 g. of 10 per cent palladium-on-charcoal catalyst until one mole equivalent of hydrogen was absorbed (about 30 min. required), there was obtained 8.0 g. of crude 3,4-bis(ptoluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a pulvurulent solid which by treatment with an excess of 10 per cent ammonium hydroxide was converted to the free base, which weighed 4.3 g. and melted at 84C. This base was converted to its methanesulfonic acid salt (4.3 g.), a white crystalline powder which melted at 170172C. (uncorr.). The methanesulfonate was soluble in dimethyl sulfoxide to the extent of at least 1 per cent; and when a 1 per cent solution of dimethyl sulfoxide was diluted with three volumes of water, no precipitate formed.

C. To a solution of 1.1 g. of 3,4-bis(ptoluy1oxy)pheny1 tert-butylaminomethyl ketone methanesulfonate (m.p. l187C. (uncorr.) obtained by reacting the free base with methanesulfonic acid) in 20 m1. of anhydrous methyl alcohol at 5C. under an atmosphere of nitrogen there was added with stirring mg. of dry sodium borohydride. After 5 minutes the reaction was quenched with about fifteen drops of glacial acetic acid to bring the pH of the mixture to approximately 6. The mixture was evaporated to dryness, diluted with 200 ml. of diethyl ether, and washed with 100 ml. of 5 per cent aqueous sodium bicarbonate solution, followed by washing successively with water and water saturated with sodium chloride. The aqueous washes were combined and extracted with diethyl ether and this extract was combined with the ethereal solution, dried over sodium sulfate, and evaporated to yield 1 g. of colorless oil. This oil, which was 3,4-bis( ptoluyloxy )-a1pha-(tert-butylaminomethyl )benzyl alcohol, was diluted with 70 ml. of anhydrous diethyl ether and 0.14 ml. of methanesulfonic acid was added. A white precipitate formed on cooling. The mixture was concentrated to a volume of about 25 and filtered. The white crystalline solid thus obtained, which weighted 1. l g., was 3,4-bis( p-toluyloxy )-alpha-( tertbutylaminomethyl)benzy1 alcohol methanesulfonate, identical with the product described above in part B. The corresponding acetate salt was a white solid, mp. C. (uncorr.).

EXAMPLE 3 1 Following the procedure described above in Example 29A but using p-tert-butylbenzoyl chloride instead of benzoyl chloride there is obtained b 3,4-bis(p-tertbutylbenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is caralytically hydrogenated, using the procedure described above in Example 298, there is obtained 3,4-bis(p-tert-butylbenzoyloxy)alpha-(tertbutylaminomethyl )-benzyl alcohol hydrochloride.

EXAMPLE 32 Following the procedure described above in Example 29A but using 2-methyl-4-ethylbenzoyl chloride instead of benzoyl chloride there is obtained 3,4-bis(2- methyl-4-ethylbenzoyloxy)phenyl tertbutylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 298, there is obtained 3,4-bis(2- methyl-4-ethylbenzoyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 33 A. Proceeding in a manner similar to that described in Example 30A above, 26 g. of 3,4-dihydroxyphenyl tert-butylamino methyl ketone hydrochloride was reacted with 17 g. of sodium methoxide in 200 ml. of N,N-dimethylformamide, and the resulting sodium phenolate salt was interacted with p-anisoyl chloride to yield 12.3 g. of 3,4-bis(p-anisoyloxy)phenyl tertbutylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 205208C. (uncorr.).

B. By catalytic hydrogenation of 12.0 g. of 3,4-bis( panisoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 300 ml. of anhydrous ethyl alcohol in the presence of 2.0 g. of per cent palladium-oncharcoal catalyst there was obtained 6.2 g. of 3,4-bis(panisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at 165C. (uncorr. The solubility of this salt in polyethyleneglycol 200 at C. was less than 1 per cent. When 1 per cent solutions of this salt in each of dimethyl sulfoxide and glycerol formal were diluted with 3 volumes of water, no precipitate formed.

EXAMPLE 34 Following the procedure described above in Example A but using pethoxybenzoyl chloride instead of ptoluyl chloride there is obtained 3,4-bis(p-ethoxybenzoyloxy)phenyl tert-butylaminornethyl'ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 308, there is obtained 3,4- bis(p-ethoxybenzoyloxy)-alpha-(tert butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 35 Following the procedure described above in Example 30A but using p-acetamidobenzoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(pacetamidobenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrobromic acid there is obtained the hydrobromide salt. When this hydrobromide is catalytically hydrogenated. using the procedure described above in Example 30B,

there is obtained 3,4-bis(p-acetamidobenzoyloxy)- alpha-(tert-butylaminomethyl)benzyl alcohol hydrobromide.

EXAMPLE 36 When 3,4,5 tributoxybenzoyl chloride is substituted for the p-toluyl chloride in the procedure described in Example 30A above, there is obtained 3,4-bis(3,4,5- tributoxybenzoyloxy)phenyl tert-butylaminornethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using the procedure described in Example 303 above, there is obtained 3 ,4-bis( 3 ,4,5-tributoxybenzoyloxy)-alpha- (tert-butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 37 EXAMPLE 38 Following the procedure described above in Example 30A but using 2-bromo-5-chlorobenzoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(2- bromo-S-chlorobenzoyloxy)phenyl tertbutylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 3013, there is obtained 3,4-bis(2- bromo-S-chlorobenzoyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

7 EXAMPLE 39 Following the procedure described above in Example 30A but using 2,3,4-trichlorobenzoyl chloride instead of p-toluyl' chloride there is obtained 3,4-bis(2,3,4 trichlorobenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate saltv When this methanesulfonate is catalytically hydrogenated, using the procedure described above in Example 3013, there is obtained 3,4-bis(2,3,4- trichlorobenzoyloxy)alpha-(tertbutylaminomethyl)benzyl alcohol methanesulfonate.

EXAMPLE 40 When 2,3,5-trifluorobenzoyl chloride is substituted for the p-toluyl chloride in the procedure described in Example 30A above, the product obtained is 3,4- bis( 2,3,S-trifluorobenzoyloxy )phenyl tertbutylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained by hydrochloride salt. When this hydrochloride is catalytically hydrogenated using the procedure described in Example 308 above, there is obtained 3,4-bis(2,3,5- trifluorobenzoyloxy)-alpha(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 41 When 3,5-bis(trifiuoromethyl)benzoyl chloride is substituted for the p-toluyl chloride in the procedure described in Example 30A above, the product obtained is 3,4-bis[3,5-bis-(trifluoromethyl)benzoyloxy]phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using the procedure described in Example 308 above, there is obtained 3,4- bis[ 3 ,5(trifluoromethyl)benzoyloxy]-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 42 Following the procedure described above in Example 30A but using Z-ethoxy-S-fluorobenzoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(2- ethoxy-S-fluorobenzoyloxy)phenyl tertbutylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3,4-bis(2- ethoxy-S-fiuorobenzoyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 43 Following the procedure described above in Example 30A but using 2,6-dimethyl-4-propoxybenzoyl chloride instead of p-toluyl chloride there is obtained 3,4- bis(2,6-dimethyl-4-propoxybenzoyloxy)phenyl tertbutylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hy* drochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 308, there is obtained 3,4-bis(2,6- dimethyl-4-propoxybenzoyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 44 When 2-chloro-3-methoxy-4-methylbenzoyl chloride is substituted for the p-toluyl chloride in the procedure described in Example 30A above, the product obtained is 3,4-bis(Z-chloro-3-meth0xy-4-methylbenzoyloxy)- phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using the procedure described in Example 308 above, there is obtained 3,4- bis( Z-chloro-3-methoxy-4-methylbenzoyloxy )-alpha- (tert-butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 45 Following the procedure described above in Example 30A but using phenylacetyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(phenylacetoxy)- phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 308, there is obtained 3,4 bis(phenylacetoxy)-alpha-(tert butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 46 Following the procedure described above in Example 30A but using p-ethylphenylacetyl chloride instead of p-toluyl chloride there is obtained 3,4 bis(p-ethylphenylacetoxy)phenyl tert-b'utylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3,4-bis(p-ethylphenylacetoxy)-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 47 Following the procedure described above in Example 30A but using 2,5-dimethyl-4-methoxyphenylacetyl chloride instead of p-toluy1 chloride there is obtained 3 ,4-bis( 2,5-dimethyl-4-methoxyphenylacetoxy )phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 3013, there is obtained 3,4-bis(2,5- dimethyl-4-methoxyphenylacetoxy)alpha-(tert butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 48 Following the procedure described above in Example 30A but using 2-bromo-4,S-diethoxyphenylacetyl chloride instead of p-toluyl chloride there is obtained 3,4 bis(2-bromo-4,S-diethoxyphenylacetoxy)phenyl tertbutylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure decribed above in Example 308, there is obtained 3,4-bis(2 bromo-4,5-diethoxyphenylacetoxy)-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 49 Following the procedure described above in Example 30A but using B-phenylpropi-onyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(,8-phenylpropionyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the proce dure described above in Example 308, there is obtained 3,4bis(,B-phenylpropionyloxy )-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 50 EXAMPLE 5 1 Following the procedure described above in Example 30A but using 2-naphthalenecarbonyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(2- naphthalenecarbonyloxy)phenyl tertbutylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 308, there is obtained 3,4-bis(2- naphthalenecarbonyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 52 Following the procedure described above in Example 30A but using phenoxyacetyl chloride instead of ptoluyl chloride there is obtained 3,4bis( phenoxyacetoxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochlo ride is catalytically hydrogenated, using the procedure described above in Example 308, there is obtained 3,4- bis(phenoxyacetoxy)-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 53 Following the procedure described above in Example 30A but using p-diethylaminobenzoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(pdiethylaminobenzoyloxy)phenyl tertbutylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3,4-bis-(pdiethylaminobenzoyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 54 Following the procedure described above in Example 30A but using nicotinoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(nicotinoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3,4- bis( nicotinoyloxy )-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 55 Following the procedure described above in Example 2A but using crotonoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(crotonoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is reduced with sodium borohydride, using the procedure described above in Example 30C, there is obtained 3,4- bis( crotonoylox y )-alpha-( tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 56 Following the procedure described above in Examle 2A but using 9-octadecenoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(9- octadecenoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is reduced with sodium borohydride using the procedure described above in Example 30C, there is obtained 3,4-bis(9-octadecenoyloxy)-alpha- (tert-butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 57 Following the procedure described above in Example 2A but using 5,13-docosadienoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(5,l3- docosadienoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is reduced with sodium borohydride, using the procedure described above in Example 30C, there is obtained 3,4-bis(5,l 3-docosadienoyloxy)- alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 58 A. Under an atmosphere of nitrogen, 8.1 g. of sodium methoxide was added to 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of dimethylformamide and 50 ml. of solvent was distilled from the reaction mixture under reduced pressure. Then under an atmosphere of nitrogen 7.8 g. of isovaleryl chloride was dripped in at 2025C. and the reaction mixture was stirred at 25C. for 1 hour. The solvent was distilled off under reduced pressure and the resulting residue was taken up in a mixture of 500 ml. of water, 3 ml. of 35 per cent aqueous sodium hydroxide solution, and 200 ml. of diethyl ether. The ether layer was separated and discarded. The aqueous layer was acidified with acetic acid and the precipitate which formed was collected on a filter and washed well with water and n-hexane. There was thus obtained 12 g. of 3-hydroxy-4-( isovaleryloxy )phenyl tertbutylaminomethyl ketone. This base was slurried in 500 ml. of anhydrous ethyl alcohol and with stirring there was added 68 per cent methanesulfonic acid in an amount (5 ml.) sufficient to produce a persistent acidic reaction in the slurry, which was then stirred until a heavy precipitate formed. The precipitate was collected on a filter and washed with ethyl alcohol and diethyl ether. There was thus obtained 8.1 g. of 3- hydroxy-4-(isovaleryloxy)phenyl tertbutylaminomethyl ketone methanesulfonate as a white crystalline solid which melted at 242245C.(dec.- )(uncorr.).

B. By catalytic hydrogenation of 8.1 g. of 3-hydroxy- 4-(isovaleryloxy)phenyl tert-butylaminomethyl ketone methanesulfonate suspended in 250 ml. of per cent ethyl alcohol in the presence of 3.0 g. of 10 per cent palladium-on-charcoal catalyst there was obtained 4.8 g. of 3-hydroxy-4-(isovaleryloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at 148l50C- .(uncorr.). The solubility of this salt in water at 25C was at least 5 per cent.

EXAMPLE 59 A. Following a procedure similar to that described in Example 58A above, 260 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 170 g. of sodium methoxide in 2 kg. of N,N-dimethylformamide, and the resulting sodium phenolate was interacted with g. of pivalyl chloride to yield 250 g. of 3-hydroxy-4-(pivalyloxy)phenyl tertbutylaminomethyl ketone. The hydrochloride of this base was a white crystalline solid which melted at 268270C. (dec.)(uncorr.), and the methanesulfonate of the base was a white crystalline solid which melted at 260263C. (dec.)(uncorr.).

B. By catalytic hydrogenation of 18 g. of 3-hydroxy- 4-(pivalyloxy)phenyl ten-butylaminomethyl ketone methanesulfonate suspended in one liter of 95 per cent ethyl alcohol in the presence of 3 g. of per cent palladium-on-charcoal catalyst there was obtained 10.0 g. of 3-hydroxy-4-(pivalyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at l75l77C- .(uncorr.).

EXAMPLE 60 By interacting 13 g. of 3,4-dihydroxyphenyl tertbutylaminomethyl ketone hydrochloride with 8 ml. of 3,3-dimethylbutanoyl chloride in 35 ml. of trifiuoroacetic acid at room temperature, there was obtained 3-hydroxy-4-( 3,3-dimethylbutanoyloxy )phenyl tertbutylaminomethyl ketone trifiuoroacetate which was converted to the free base by treatment with ammonium hydroxide; and by interaction of this base with methanesulfonic acid there was obtained the methanesulfonate salt, m.p. 240245C. (dec.). When this methanesulfonate was catalytically hydrogenated, using the procedure described above in Example 58B, there was obtained 3-hydroxy-4-( 3 ,3- dimethylbutanoyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at l76l78C- .(uncorr.)

EXAMPLE 61 Following the procedure described above in Example 58A but using 7,7-dimethyloctanoyl chloride instead of isovaleryl chloride there is obtained 3-hydroxy-4-(7,7- dimethyloctanoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 588, there is obtained 3-hydroxy-4-(7,7-dimethyloctanoyloxy)- alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 62 When dodecanoyl chloride is substituted for the isovaleryl chloride in the procedure described in Example 58A above, the product obtained is 3-hydroxy-4- dodecanoyloxy )phenyl tert-butylaminomethyl ketone; by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using the proce dure described in Example 58B above, there is ob- -.tained 3-hydroxy-4-(dodecanoyloxy)-alpha-(tertbutylaminomethyhbenzyl alcohol hydrochloride.

EXAMPLE 63 When 2,2,17, l 7-tetramethyloctadecanoyl chloride is substituted for the isovaleryl chloride in the procedure described in Example 58A above, the product obtained is 3-hydroxy-4-( 2,2, l 7, l 7-tetramethyloctadecanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using the procedure described in Example 588 above, there is obtained 3-hydroxy-4(2,2,l7,l7-

tetramethyloctadecanoyloxy )-alpha-( tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 64 Following the procedure described above in Example 58A but using l-methylcyclopropanecarbonyl chloride instead of isovaleryl chloride there is obtained 3- hydroxy-4-( l-methylcyclopropanecarbonyloxy )phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 588, there is obtained 3-hydroxy-4- 1-methylcyclopropanecarbonyloxy )-alpha-( tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 65 Following the procedure described above in Example 58A but using cycloheptanecarbonyl chloride instead of isovaleryl chloride there is obtained 3-hydroxy-4- (cycloheptanecarbonyloxy)phenyl tertbutylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 583, there is obtained 3-hydroxy-4- (cycloheptanecarbonyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 66 Following the procedure described above in Example 58A but using cyclohexaneacetyl chloride instead of isovaleryl chloride there is obtained 3-hydroxy-4- (cyclohexaneacetoxy )phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 58B, there is obtained 3-hydroxy-4-(cyclohexaneacetoxy)-alpha- (tert-butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 67 Following the procedure described above in Example 58A but using cyclopentanepropionyl chloride instead of isovaleryl chloride there is obtained 3-hydroxy-4- (cyclopentanepropionyloxy)phenyl tertbutylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 588, there is. obtained 3-hydroxy-4- (cyclopentanepropionyloxy )-alpha-( tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 68 Following the procedure described above in Example 58A but using nicotinoyl chloride instead of isovaleryl chloride there is obtained 3-hydroxy-4- (nicotinoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 58B, there is obtained 3 -hydroxy-4-( nicotinoyloxy )-alpha-( tertbutylaminomethyl)'benzyl alcohol hydrochloride.

EXAMPLE 69 A. Following a procedure similar to that described in Example 58A above, 13 g. of 3,4-dihydroxyphenyl tertbutylaminomethyl ketone hydrochloride was reacted with 8.1 g. of sodium methoxide in 200 ml. c N,N-dimethylformamide, and the resulting sodium phenolate was interacted with 8.5 g. of p-toluyl chloride to yield 3-hydroxy-4-(p-toluyloxy)phenyl tertbutylaminomethyl ketone. This base was converted to the methanesulfonate by treatment, in 200 ml. of warm N,N-dimethylformamide, with methanesulfonic acid. The 3-hydroxy-4-(p-toluyloxy)phenyl tertbutylaminomethyl ketone methanesulfonate thus obtained was a white crystalline solid which weighed 12 g. and melted at 265C. (dec.)(uncorr.).

B. By catalytic hydrogenation of 12 g. of 3-hydroxy- 4-( p-toluyloxy)phenyl tert-butylaminomethyl ketone methanesulfonate in 1 liter of 95 per cent ethyl alcohol in the presence of 4 g. of palladium-on-charcoal catalyst there was obtained 7.4 g. of 3-hydroxy-4-(ptoluyloxy )-alpha-( tert-butylaminomethyl )benzyl alcohol methanesulfonate as a white crystalline powder which melted at 203205C. (uncorr.). The solubility of this salt in water at 25C. was at least per cent.

EXAMPLE 70 Following the procedure described above in Example 58A but using 2,3,4-trichlorobenzoyl chloride instead of isovaleryl chloride there is obtained 3-hydroxy-4- (2 ,3 ,4-trichlorobenzoyloxy )phenyl tertbutylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 58B, there is obtained 3-hydroxy-4- (2,3 ,4-trichlorobenzoyloxy )-alpha-( tertbutylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 71 A. Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4- (pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with isovaleryl chloride there is obtained 3-(isovaleryloxy)-4- (pivalyloxy)phenyl tert-butylaminomethyl ketone, which reacts with hydrochloric acid to yield the hydrochloride salt as a white crystalline solid, mp. 2l6-220C. (uncorr.).

B. By catalytic hydrogenation of 7.7 g. of 3- (isovaleryloxy)-4-( pivalyloxy)phenyl tertbutylaminomethyl ketone hydrochloride in 200 ml. of 95 per cent ethyl alcohol in the presence of 2.0 g. of per cent palladium-on-charcoal catalyst there was obtained 6.1 g. of 3-(isovaleryloxy)-4-(pivalyloxy)-alpha (tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at 202204C. (uncorr.). The solubility of this salt in water at C. was at least 5 per cent.

EXAMPLE 72 Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4- (pivalyloxy )phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with pivalyl chloride there is obtained 3,4-bis(pivalyloxy)phenyl tert-butylaminomethyl ketone, which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained 3,4-bis(pivalyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride. The ketone intermediate and the alcohol product obtained in this manner are identical with the ketone and the alcohol described above in Example 5A and 5B, respectively.

EXAMPLE 73 Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4- (pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with decanoyl chloride there is obtained 3-(decanoyloxy)-4- (pivalyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 23, there is obtained 3-( decanoyloxy)-4- (pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 74 EXAMPLE 75 Following a procedure similar to that described in Example 30A above, when 3-hydroxy-4- (pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 3,4,5-trimethoxybenzoyl chloride there is obtained 3- (3 ,4,5-trimethoxybenzoyloxy )-4-( pivalyloxy )phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3-( 3 ,4,5-trimethoxybenzoyloxy )-4- (pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 76 Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(ptoluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with isovaleryl chloride there is obtained 3-(isovaleryloxy)-4- (p-toluyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 23, there is obtained 3-(isovaleryloxy)-4-(ptoluyloxy )-alpha-(tert-butylaminomethyl )benzyl alcohol hydrochloride.

EXAMPLE 77 Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(ptoluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is interacted with 3,3-dimethylbutanecarbonyl chloride there is obtained 3-( 3,3-dimethylbutanecarbonyloxy)-4-( ptoluyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 28, there is obtained 3-( 3 ,3- dimethylbutanecarbonyloxy)-4-(p-toluyl0xy)-alpha (tert-butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 78 Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(ptoluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with docosanoyl chloride there is obtained 3- (docosanoyloxy)-4-(p-toluyloxy)phenyl tertbutylaminomethyl ketone which reacts with methanesulfonic acid to yield the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using the procedure described above in Example 23, there is obtained 3-(docosanoyloxy)-4-(prtoluyloxy)- alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.

EXAMPLE 79 EXAMPLE 80 Following a procedure similar to that described above in Example 30A, when 3-hydroxy-4-(ptoluyloxy)phenyl tert-butylaminomethyl ketone is interacted with nicotinoyl chloride, there is obtained 3- (nicotinoyloxy)-4-( p-toluyloxy )phenyl tertbutylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3- 30 nicotinoyloxy-4-(p-toluyloxy -alpha-(tert- -butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 81 Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4- (nicotinoyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 9-octadecenoyl chloride there is obtained 3-(9- octadecenoyloxy )-4-( nicotinoyloxy )phenyl tertbutylaminomethyl ketone which reacts with methanesulfonic acid to yield the methanesulfonate salt. When this methanesulfonate is reduced with sodium borohydride using the procedure described above in Example 30C, there is obtained 3-(9-octadecenoyloxy)-4- (nicotinoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.

EXAMPLE 82 Following a procedure similar to that described in Example 1 3A above, when 3-hydroxy4- (isovaleryloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with l,3-dimethylcyclobutanecarbonyl chloride there is obtained 3-( l,3-dimethylcyc1obutanecarbonyloxy )-4- (isovaleryloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 138, there is obtained 3-( 1,3- dimethylcyclobutanecarbonyloxy)-4-(isovaleryloxy) alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 83 A. Under an atmosphere of nitrogen, 8.4 g. of sodium methoxide is added with vigorous stirring to 16.8 g. of 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride suspended in 200 ml. of N,N-dimethylformamide. About 20 ml. of solvent is distilled from the reaction mixture under reduced pressure to remove methyl alcohol. Then, under an atmosphere of nitrogen, 16 g. of 2,2-dimethylpentanoyl chloride is dripped in slowly at 5C. with vigorous stirring, and stirring is continued for one hour after all of the acid chloride has been added. The solvent is distilled off under reduced pressure and the resulting residue is partitioned between water and diethyl ether. The ether layer is separated and washed with water, and the ether is distilled off to yield 3,4-bis(2,2-dimethylpentanoyloxy)phenyl isopropylaminomethyl ketone. This product is treated with hydrochloric acid in isopropyl alcohol, and the solvent is evaporated to yield 3,4-bis(2,2-dimethylpentanoyloxy)phenyl isopropylaminomethyl ketone hydrochloride.

B. A solution of 3,4-bis(2,Z-dimethylpentanoyloxy)- phenyl isopropylaminomethyl ketone hydrochloride in anhydrous ethyl alcohol is hydrogenated in the presence of 10 per cent palladium-on-charcoal hydrogenation catalyst until one mole equivalent of hydrogen has been absorbed. The hydrogenation mixture is filtered to remove the catalyst, the solvent is evaporated from the filtrate, and isopropyl acetate is added to the residue and then distilled off. The residue thus obtained is dissolved in boiling isopropyl acetate and the solution thus obtained is cooled. The precipitate which forms is collected on a filter, washed with isopropyl acetate and with diethyl ether, and dried at 70C. There is thus obtained 3,4-bis(2,2-dimethylpentanoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride as a white crystalline powder.

EXAMPLE 84 EXAMPLE 85 When hexadecanoyl chloride is substituted for the isobutyryl chloride in the procedure described in Example 2A above, the product obtained is 3,4-bis(hexadecanoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated using the procedure described in Example 2B above, there is obtained 3,4-bis(hexadecanoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol methanesulfonate.

EXAMPLE 86 When docosanoyl chloride is substituted for the isobutyryl chloride in the procedure described in Example 2A above, the product obtained is 3,4-bis(- docosanoyloxy)phenyl isopropylaminomethyl ketone; and by interaction with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated using a procedure similar to that described in Example 28 above, there is obtained 3,4-bis-(docosanoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol methanesulfonate.

EXAMPLE 87 Following the procedure described above in Example 2A but using 4-methylcyclohexaneacetyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(4- methylcyclohexaneacetoxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hy drochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3,4- bis( 4-methylcyclohexaneacetoxy )-alpha-( isopropylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 88 When cycloheptanecarbonyl chloride is substituted for the isobutyryl chloride in the procedure described in Example 2A above, the product obtained is 3,4- bis(cycloheptanecarbonyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using a procedure similar to that described in Example 2B above, there is obtained 3,4-

bis( cycloheptanecarbonyloxy )-alpha-( isopropylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 89 When p-toluyl chloride is substituted for the isobutyryl chloride in the procedure described in Example 2A above, the acylation product obtained is 3,4-bis-(ptoluyloxy)phenyl isopropylaminomethyl ketone, m.p. 8285C.(uncorr.). This base was treated with trifluoroacetic acid to yield the trifluoroacetate salt as a white crystalline solid which melted at 193l 95C.(uncorr. When 24 g. of this trifluoroacetate was catalytically hydrogenated using a procedure similar to that described in Example 28 above there was obtained 19.5 g. of 3,4- bis(p-toluyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol trifluoroacetate, m.p. 1 151 17C. (uncorr.). A 15 g. portion of this salt was converted to the free base which was then treated with methanesulfonic acid to yield 10.5 g. of the methanesulfonate salt as a white crystalline solid which melted at 1 l41 16C.(uncorr.

EXAMPLE 90 When phenylacetyl chloride is substituted for the isobutyryl chloride in the procedure described in Example 2A above, the product obtained is 3,4-bis(- phenylacetoxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using a procedure similar to that described in Example 2B above, there is obtained 3,4-bis(phenylacetoxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 91 Following the procedure described above in Example 2A but using 3,7-dimethyl-3,o-octadienoyl chloride instead of isobutyryl chloride there is obtained 3,4- bis( 3 ,7-dimethyl-3 ,6-octadienoyloxy )phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this base is reduced with sodium borohydride, using a procedure similar to that described above in Example 30C, there is obtained 3,4- bis( 3 ,7-dimethyl-3 ,6-octadienoyloxy )-alpha-( isopropylaminomethyl)benzyl alcohol. By catalytically hydrogenating 3,4-bis)3,7-dimethyl-3,6- octadienoyloxy)phenyl isopropylaminomethyl ketone methanesulfonate, using a procedure similar to that described above in Example 308, there is obtained 3,4- bis( 3 ,7-dimethyloctadecanoyloxy )-alpha-( isopropylaminomethyl)benzyl alcohol methanesulfonate.

EXAMPLE 92 When isonicotinoyl chloride is substituted for the isobutyryl chloride in the procedure described in Example 2A above, the product obtained is 3,4-bis- (isonicotinoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated using a procedure similar to that described in Example 28 above, there is obtained 3,4- bis( isonicotinoyloxy )-alpha-( isopropylaminomethyl benzyl alcohol methanesulfonate.

EXAMPLE 93 Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert.-butylaminomethyl ketone hydrochloride and octanoyl chloride instead of isovaleryl chloride, there is obtained 3hydroxy-4-(octanoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2b, there is obtained 3-hydroxy-4-(octanoyloxy)-alpha- (isopropylaminomethyl)-benzyl alcohol hydrochloride.

EXAMPLE 94 EXAMPLE 95 Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert.-butylaminomethyl ketone hydrochloride and phenoxyacetyl chloride instead of isovaleryl chloride, there is obtained 3hydroxy-4' (.phenoxyacetoxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using a procedure similar to that described above in Example 28, there is obtained 3-hydroxy-4- (phenoxyacetoxy )-alpha-(isopropylaminomethyl)benzyl alcohol methanesulfonate.

EXAMPLE 96 Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and l-naphthalenecarbonyl chloride instead of isovaleryl chloride, there is obtained 3 hydroxy-4-( l-naphthalenecarbonyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalyti cally hydrogenated, using a procedure similar to that described above in Example 28, there is obtained 3- hydroxy-4-( l-naphthalenencarbonyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 97 Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and p-toluyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(ptoluyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hyrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-( p-toluyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 98 Following a procedure similar to that described above in Example 58A but using 3,4-dihydroxyphenyl isopropylamino-methyl ketone hydrochloride instead of 3,4-dihyroxyphenyl tert-butylaminomethyl ketone hydrochloride, and nicotinoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4- (nicotinoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 28, there is obtained 3-hydroxy-4-(nicotinoyloxy)-alpha- (isopropylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 99 Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 2,3,4-trimethylbenzoyl chloride instead of isovaleryl chloride, there is obtained 3- hydroxy-4( 2,3,4-trimethylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hy drochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3- hydroxy-4-(2,3,4-trimethylbenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 100 Following the procedure described above in Example 58A, but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4.-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and m-dimethylarninobenzoyl chloride instead of isovaleryl chloride, there is obtained 3- hydroxy-4-(m-dimethylaminobenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 28, there is obtained 3- hydroxy-4-( m-dimethylaminobenzoyloxy )-alpha-( isopropylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 101 Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and o-propionamidobenzoyl chloride instead of isovaleryl chloride, there is obtained 3- hydroxy-4-(o-propionamidobenzzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using a procedure similar to that described above in Example 28, there is obtained 3-hydroxy-4-(o-propionamidobenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol and methanesulfonate.

EXAMPLE 102 Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 2-chloro-3-methoxy-4-methylbenzoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-( 2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 28, there is obtained 3-hydroxy-4-(2-chloro-3-methoxy-4- methylbenzoyloxy )-alpha-( isopropylaminomethyl benzyl alcohol hydrochloride.

EXAMPLE 103 Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 10,1 3-octadecadienoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(10,13-octadec a dienoyloxy) phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is reduced with sodium borohydride, using a procedure similar to that described above in Example 30C, there is obtained 3-hydroxy-4-( 10,13-octadecadienoyloxy)- alpha-( isopropylaminomethyl )benzyl alcohol methanesulfonate. By catalytic hydrogenation of 3-hydroxy-4- 10,1 3-octadienoyloxy)phenyl isopropylaminomethyl ketone methanesulfonate, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(octadecanoyloxy)-alpha-(isopropylaminomethyl)benzyl methanesulfonate.

EXAMPLE 104 Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4- (isovaleryloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 3,3-dimethylpentanoyl chloride there is obtained 3- (3,3-dimethylpentanoyloxy)-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hdyrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3- (3 ,3-dimethylpentanoyloxy )-4-( isovaleryloxy )-alpha- (isopropylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 105 Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hy- EXAMPLE 106 Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(ptoluyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with picolinoyl chloride, there is obtained 3-(picolinoyloxy)-4- (p-toluyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, usign a procedure similar to that described above in Example 2B, there is obtained 3-(picolinoyloxy)-4-(ptoluyloxy)- alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 107 Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(2-chloro-3- methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with isovaleryl chloride there is obtained 3-(isovaleryloxy)-4-(2-chloro-3- methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 28, there is obtained 3- (isovaleryloxy )-4-( 2-chloro-3-methoxy-4- methylbenzoyloxy)-alpha-(isopropylaminomethyl)- benzyl alcohol hydrochloride.

EXAMPLE 108 Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(phenoxyacetoxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with cyclohexanecarbonyl chloride there is obtained 3- (cyclohexanecarbonyloxy )-4-( phenoxyacetoxy )phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 28, there is obtained 3- (cyclohexanecarbonyloxy )-4-( phenoxyacetoxy )-alpha- (isopropylaminomethyl )-benzyl alcohol hydrochloride.

EXAMPLE 109 Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(2ch1oro-3- methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate is reacted with 3.3-dimethylheptadecanoyl chloride there is obtained 3-(3.3- dimethylheptadecanoyloxy)-4-(2-chloro-3-methoxy-4- methylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 28, there is obtained 3-( 3 ,3- dimethylheptadecanoyloxy -4-( 2-chloro- 3methoxy-4- methylbenzoyloxy)-alpha-(isopropylaminomethyl)- benzyl alcohol hydrochloride.

EXAMPLE 1 Following a procedure similar to that described in Example 2A above when 3-hydroxy-4-(3,3- dimethylcyclobutanecarbonyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 2,5-hexadienoyl chloride there is obtained 3-(2,5-hexadienoyloxy)-4 (3 ,3dimethylcyclobutanecarbonyloxy )phenyl isopropylaminomethyl ketone which reacts wthg hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is reduced with sodium borohydride, using a procedure similar to that described above in Example 30C, there is obtained 3-(2,5-hexadienoyloxy)- 4-( 3 ,3-dimethylcyclobutanecarbonyloxy )-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.

EXAMPLE 1 l 1 A mixture of 13 g. of 3,4-dihydroxyphenyl tertbutylaminomethyl ketone hydrochloride, m. of otoluyl chloride, and 35 ml. of trifluoroacetic acid was heated for minutes on a steam bath. The reaction mixture was concentrated under reduced pressure, and the resulting residue crystallized. This solid, which was crude 3,4-bis(o-toluyloxy)phenyl tertbutylaminomethyl ketone trifluoroacetate, was slurried in anhydrous ethyl ether and the slurry was made basic by treatment with ammonium hydroxide. The ether layer was separated and washed first with dilute aqueous sodium hydroxide solution and then with water. The ether solution was filtered and the filtrate was slurried with 4.5 g. of methanesulfonic acid in 50 ml. ofisopropyl alcohol. The crystalline solid which precipitated was collected on a filter and recrystallized from 100 ml. of isopropyl alcohol and dried at 70C. There was thus obtained 15.8 g. of 3,4-bis(o-toluyloxy)phenyl tertbutylaminomethyl ketone methanesulfonate as a white crystalline solid which melted at l34-l37C. (dec.- )(uncorr.). When this methanesulfonate( 15.5 g.) was catalytically hydrogenated, using a procedure similar to that described above in Example 303, there was obtained 12.8 g. of 3,4-bis(o-toluyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at l5l-l53C. (uncorr.).

EXAMPLE 1 12 Following a procedure similar to that described above in Example 111 but using m-toluyl chloride instead of o-toluyl chloride, there was obtained 14 g. of 3,4-bis(m-toluyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 215218C. When 19 g. of this hydrochloride (5 g. of which was obtained from a second run) was catalytically hydrogenated, using a procedure similar to that described above in Example 30B, there was obtained 3,4-bis(m-toluyloxy)alpha-(tertbutylaminomethyl)benzyl alcohol hydrochloride which was converted to the free base and then to the methanesulfonate, a white crystalline solid which weighed 12.0 g. and melted at C. (uncorr.).

EXAMPLE 1 l 3 Following a procedure similar to that described above in Example 111, 14 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 27 g. of 2,3-dimethlylbenzoyl chloride in 50 ml. of trifluoroacetic acid to yield 3,4-bis(2,4- dimethylbenzoyloxy)phenyl tert-butylaminomethyl ketone trifluoroacetate. This salt was converted to the free base by treatment with sodium hydroxide solution and the free base was interacted with methanesulfonic acid to yield 22 g. of 3,4-bis(2.,4-dimethylbenzoyloxy)- phenyl tert-butylaminomethyl ketone methanesulfonate as a white crystalline solid which melted at 120-123C. (dec.)(uncorr.). This salt (20 g.) was catalytically hydrogenated in N,N-dimethylformamide using a procedure similar to that described above in Example 3OB, to yield 18 g. of 3,4-bis(2,4- dimethylbenzoyloxy)-alpha-(tertbutylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which. melted at l72C- .(uncorr.).

EXAMPLE 1 14 Following a procedure similar to that described above in Example 111, 20 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 37 g. of 2,5-dimethylbenzoyl chloride in 50 ml. of trifluoroacetic acid to yield 3,4-bis(2,5- dimethylbenzoyloxy)phenyl tert-butylaminomethyl ketone trifluoroacetate. This salt was converted to the free base by treatment with ammonium hydroxide and the free base was interacted with methanesulfonic acid to yield 38 g. of 3,4-bis(2,5-dimethylbenzoyloxy)phenyl tert-butylaminomethyl ketone methanesulfonate as a white crystalline solid which melted at l34l37C. (dec.)(uncorr.). This salt (37 g.) was catalytically hydrogenated in l-I,N-dimethylformamide, using a procedure similar to that described above in Example 308. to yield 30 g. of 3,4-bis(2,5-dimethylbenzoyloxy)- alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at l56l58C. (uncorr.).

EXAMPLE 1 15 Following a procedure similar to that described above in Example 111, 20 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 37 g. of 3,4-dimethylbenzoyl chloride in 50 ml. of trifluoroacetic acid to yield 3,4-bis(3,4- dimethylbenzoyloxy)phenyl tert-butylaminomethyl ke- 

1. A COMPOUND OF THE GROUP CONSISTING OF: 3-(Y1-O-)-4-(Y-O-)PHENYL (R-NH-)(R'')METHYL KETONES HAVING THE FORMULA
 2. A 3-(Y1-O-)-4-(Y-O-)phenyl (R-NH-)(R'')methyl ketone according to claim
 1. 3. A compound according to claim 2 wherein R'' is hydrogen.
 4. A compound according to claim 3 wherein R is alkyl.
 5. A compound according to claim 4 wherein R is tert-butyl.
 6. A 3-(Y-O-CH2-)-4-(Y1-O-)phenyl (R-NH-)(R'')methyl ketone according to claim
 1. 7. A compound according to claim 6 wHerein R'' is hydrogen.
 8. A compound according to claim 7 wherein R is alkyl.
 9. A compound according to claim 8 wherein R is tert-butyl.
 10. A compound according to claim 9 wherein one of Y and Y1 is alkanoyl.
 11. A compound according to claim 9 wherein Y1 is hydrogen.
 12. A compound according to claim 5 wherein each of Y and Y1 is Z-CnH2n-CO-.
 13. A compound according to claim 12 wherein n is zero.
 14. A compound according to claim 13 wherein each of Y and Y1 is alkylbenzoyl.
 15. A compound according to claim 14 wherein each of Y and Y1 is toluyl.
 16. A compound according to claim 13 wherein each of Y and Y1 is anisoyl.
 17. A compound according to claim 5 wherein one of Y and Y1 is alkanoyl and the other is Z-CnH2n-CO-.
 18. A compound according to claim 17 wherein n is zero.
 19. A compound according to claim 18 wherein one of Y and Y1 is alkylbenzoyl.
 20. A compound according to claim 19 wherein one of Y and Y1 is toluyl.
 21. A compound according to claim 18 wherein one of Y and Y1 is anisoyl.
 22. A compound according to claim 5 wherein Y1 is hydrogen.
 23. A compound according to claim 22 wherein n is zero.
 24. A compound according to claim 23 wherein Y is toluyl.
 25. A compound according to claim 23 wherein Y is anisoyl.
 26. A compound according to claim 9 wherein each of Y and Y1 is Z-CnH2n-CO-.
 27. A compound according to claim 26 wherein n is zero. 